CARMOFUR

Details

Stereochemistry	ACHIRAL
Molecular Formula	C11H16FN3O3
Molecular Weight	257.2614
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O

InChI

InChIKey=AOCCBINRVIKJHY-UHFFFAOYSA-N

InChI=1S/C11H16FN3O3/c1-2-3-4-5-6-13-10(17)15-7-8(12)9(16)14-11(15)18/h7H,2-6H2,1H3,(H,13,17)(H,14,16,18)

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB09010
Curator's Comment: Description was created based on several sources, including http://www.google.com/patents/US20130109707 and http://www.ncbi.nlm.nih.gov/pubmed/16155120

Carmofur, also known as 5-fluoro-N-hexyl-2,4-dioxo-pyrimidine-1-carboxamide and as 1-hexylcarbamoyl-5-fluorouracil, is a pyrimidine analogue which acts as an antineoplastic agent through inhibition of thymidylate synthase. It has been used in the treatment of breast and colorectal cancer. Carmofur is approved in Japan for the treatment of cancer.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Acid ceramidase 1 Target ID: CHEMBL2331070 Sources: http://www.ncbi.nlm.nih.gov/pubmed/23301156	Inhibitor 8297		29.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Pancreatic cancer 97 Sources: http://www.ncbi.nlm.nih.gov/pubmed/1801884	Primary	Phase II 1132	Unknown Approved Use Unknown
Gastric cancer 53 Sources: http://www.ncbi.nlm.nih.gov/pubmed/2239802	Primary	Approved 8429	Carmofur Approved Use Gastric, colorectal, breast cancer Launch Date 1981
Breast cancer 434 Sources: http://www.ncbi.nlm.nih.gov/pubmed/7887639	Primary	Approved 8429	Carmofur Approved Use Gastric, colorectal, breast cancer Launch Date 1981

AUC

Value	Dose	Co-administered	Analyte	Population
6.51 μg × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/2948036	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		CARMOFUR plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
1.05 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/2948036	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		CARMOFUR plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
500 mg/m2 1 times / day multiple, oral Studied dose Dose: 500 mg/m2, 1 times / day Route: oral Route: multiple Dose: 500 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/2239802/	unhealthy, 17-70 years n = 115 Health Status: unhealthy Condition: gastrointestinal cancer Age Group: 17-70 years Sex: M+F Population Size: 115 Sources: https://pubmed.ncbi.nlm.nih.gov/2239802/	Other AEs: Bladder irritation, Flushing... Other AEs: Bladder irritation (13.9%) Flushing (10.4%) Dizziness (7%) Nausea (6.1%) Fatigue (4.3%) Thrombocytopenia (1.7%) Appetite lost (1.7%) Diarrhea (1.7%) Defecation urgency (1.7%) Hematuria (0.9%) Gastric pain (0.9%) Constipation (0.9%) Angina (0.9%) Antabuse effect (0.9%) Sources: https://pubmed.ncbi.nlm.nih.gov/2239802/
300 mg 1 times / day multiple, oral Studied dose Dose: 300 mg, 1 times / day Route: oral Route: multiple Dose: 300 mg, 1 times / day Co-administed with:: mitomycin C(6 mg/m2 IV; on the day of surgery, 1 week after surgery, and every month for 6 months after surgery) 5-fluorouracil(250 mg IV; daily for 7 days) Sources: https://pubmed.ncbi.nlm.nih.gov/16823593/	unhealthy, 49-74 years n = 587 Health Status: unhealthy Condition: colon cancer Age Group: 49-74 years Sex: M+F Population Size: 587 Sources: https://pubmed.ncbi.nlm.nih.gov/16823593/	Other AEs: Anorexia, Nausea and vomiting... Other AEs: Anorexia (grade 3, 1%) Nausea and vomiting (grade 3, 0.7%) Diarrhea (grade 3, 1%) Skin disorder (grade 3, 0.5%) Respiratory symptom (grade 3, 0.7%) Leukocytopenia (grade 3, 2.7%) Hypochromia (grade 3, 3.2%) Neutropenia (grade 3, 2.7%) Thrombocytopenia (grade 3, 3.7%) Blood urea nitrogen increased (grade 3, 1.2%) Hematuria (grade 3, 0.2%) Sources: https://pubmed.ncbi.nlm.nih.gov/16823593/
400 mg 1 times / day multiple, oral Studied dose Dose: 400 mg, 1 times / day Route: oral Route: multiple Dose: 400 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/2667512/	unhealthy, 53 years n = 1 Health Status: unhealthy Condition: ovary cancer Age Group: 53 years Sex: F Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/2667512/	Disc. AE: Leukoencephalopathy... AEs leading to discontinuation/dose reduction: Leukoencephalopathy Sources: https://pubmed.ncbi.nlm.nih.gov/2667512/
300 mg/m2 3 times / day multiple, oral MTD Dose: 300 mg/m2, 3 times / day Route: oral Route: multiple Dose: 300 mg/m2, 3 times / day Co-administed with:: raltitrexed(2.0 mg/m2 IV; on day 1 of a 21-day cycle) Sources: https://pubmed.ncbi.nlm.nih.gov/11528249/	unhealthy, Median age 60 years n = 3 Health Status: unhealthy Condition: colorectal cancer Age Group: Median age 60 years Sex: M+F Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/11528249/	DLT: Fatigue, Diarrhea... Dose limiting toxicities: Fatigue (grade 4, 33.3%) Diarrhea (grade 4, 33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/11528249/
300 mg/m2 3 times / day multiple, oral MTD Dose: 300 mg/m2, 3 times / day Route: oral Route: multiple Dose: 300 mg/m2, 3 times / day Co-administed with:: raltitrexed(2.5 mg/m2 IV; on day 1 of a 21-day cycle) Sources: https://pubmed.ncbi.nlm.nih.gov/11528249/	unhealthy, Median age 60 years n = 6 Health Status: unhealthy Condition: colorectal cancer Age Group: Median age 60 years Sex: M+F Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/11528249/	DLT: Neutropenia, Fatigue... Dose limiting toxicities: Neutropenia (grade 4, 16.7%) Fatigue (grade 4, 33.3%) Anorexia (grade 4, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/11528249/
300 mg/m2 3 times / day multiple, oral MTD Dose: 300 mg/m2, 3 times / day Route: oral Route: multiple Dose: 300 mg/m2, 3 times / day Co-administed with:: raltitrexed(3.0 mg/m2 IV; on day 1 of a 21-day cycle) Sources: https://pubmed.ncbi.nlm.nih.gov/11528249/	unhealthy, Median age 60 years n = 9 Health Status: unhealthy Condition: colorectal cancer Age Group: Median age 60 years Sex: M+F Population Size: 9 Sources: https://pubmed.ncbi.nlm.nih.gov/11528249/	DLT: Anemia, Neutropenia... Dose limiting toxicities: Anemia (grade 4, 22.2%) Neutropenia (grade 4, 11.1%) Thrombocytopenia (grade 4, 11.1%) Febrile neutropenia (grade 4, 11.1%) Fatigue (grade 4, 33.3%) Anorexia (grade 4, 22.2%) Diarrhea (grade 4, 11.1%) Mucositis (grade 4, 11.1%) Sources: https://pubmed.ncbi.nlm.nih.gov/11528249/
400 mg/m2 3 times / day multiple, oral MTD Dose: 400 mg/m2, 3 times / day Route: oral Route: multiple Dose: 400 mg/m2, 3 times / day Co-administed with:: raltitrexed(3.0 mg/m2 IV; on day 1 of a 21-day cycle) Sources: https://pubmed.ncbi.nlm.nih.gov/11528249/	unhealthy, Median age 60 years n = 9 Health Status: unhealthy Condition: colorectal cancer Age Group: Median age 60 years Sex: M+F Population Size: 9 Sources: https://pubmed.ncbi.nlm.nih.gov/11528249/	DLT: Fatigue, Leukopenia... Dose limiting toxicities: Fatigue (grade 4, 44.4%) Leukopenia (grade 4, 22.2%) Neutropenia (grade 4, 11.1%) Febrile neutropenia (grade 4, 22.2%) Anorexia (grade 4, 11.1%) Diarrhea (grade 4, 44.4%) Neurological symptoms NOS (grade 4, 11.1%) Sources: https://pubmed.ncbi.nlm.nih.gov/11528249/

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OATP1B3 706 OATP1B1 788	AC1/2 1

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
OATP1B1 803	inhibitor 3277 Sources: https://molpharm.aspetjournals.org/content/83/6/1257 Page: -	no
OATP1B3 715	inhibitor 3277 Sources: https://molpharm.aspetjournals.org/content/83/6/1257 Page: -	no

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
AC1/2 1	substrate 3367 Sources: https://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.8b01723/suppl_file/jm8b01723_si_001.pdf Page: -	yes

PubMed

Title	Date	PubMed
Phase I study of a new antitumor drug, 1-hexylcarbamoyl-5-fluorouracil (HCFU), administered orally: an HCFU clinical study group report.	1980 Aug-Sep	7448823
Subacute leucoencephalopathy induced by carmofur, a 5-fluorouracil derivative.	1987 Aug	3309192
[A case of leukoencephalopathy caused by HCFU].	1988 May	3379758
[Clinical effects of carmofur (Mifurol) on advanced and recurrent breast cancer in a cooperative study. Research association for re-evaluation of direct effects of Mifurol on breast cancer].	1995 Mar	7887639
Carmofur-induced leukoencephalopathy: MRI.	1995 Nov	8748897
Diffusion-weighted MR imaging of Carmofur-induced leukoencephalopathy.	2001	11734966
A phase I study of raltitrexed (Tomudex) combined with carmofur in metastatic colorectal cancer.	2001	11528249
Optimal duration of oral adjuvant chemotherapy with Carmofur in the colorectal cancer patients: the Kansai Carmofur Study Group trial III.	2001 Aug	11445841
[Inhibition of HCFU absorption after resection for gastric cancer--application of hydroxyaluminium gel].	2001 Jun	11432348
5-fluorouracil-induced leukoencephalopathy in patients with breast cancer.	2001 Jun	11410695
Adjuvant chemotherapy after resection of hepatocellular carcinoma causes deterioration of long-term prognosis in cirrhotic patients: metaanalysis of three randomized controlled trials.	2001 Jun 15	11413528
Apoptosis and p53 overexpression in human rectal cancer; relationship with response to hyperthermo-chemo-radiotherapy.	2001 May-Jun	11501834
An individual patient data meta-analysis of long supported adjuvant chemotherapy with oral carmofur in patients with curatively resected colorectal cancer.	2001 May-Jun	11295105
Plasma, intestine and tumor levels of 5-fluorouracil in mice bearing L1210 ascites tumor following oral administration of 5-fluorouracil, UFT (mixed compound of tegafur and uracil), carmofur and 5'-deoxy-5-fluorouridine.	2001 Nov	11725974
[A case of reversible carmofur-induced leukoencephalopathy].	2001 Oct	11725511
[Neo-adjuvant chemotherapy with carmofur for colorectal cancer--a multi-institutional randomized controlled study].	2002 Nov	12465390
Raltitrexed treatment promotes systemic inflammatory reaction in patients with colorectal carcinoma.	2002 Sep 9	12237767
[Multicenter comparative study of the recurrence-inhibitory effect of oral fluoropyrimidine drugs in patients with colorectal cancer following curative resection].	2005 Jul	16044962
An individual patient data meta-analysis of adjuvant therapy with carmofur in patients with curatively resected colon cancer.	2005 Sep	16155120
S-1 (TS-1) maintained complete response for approximately 10 years in a case of metastatic breast cancer.	2006	16755122
Delivery of hydrophobised 5-fluorouracil derivative to brain tissue through intravenous route using surface modified nanogels.	2006 Feb	16608735
Significance of histologic type of primary lesion and metastatic lymph nodes as a prognostic factor in stage III colon cancer.	2006 Jul	16625329
[Adjuvant chemotherapy for colorectal cancer].	2006 Mar	16531709
[Drug-induced leukoencephalopathy].	2007 Oct 28	18074566
Immunochemotherapy with PSK and fluoropyrimidines improves long-term prognosis for curatively resected colorectal cancer.	2008 Aug	18771350
[Leukoencephalopathy caused by antineoplastic drugs].	2008 Feb	18306661

Patents

Sample Use Guides

In Vivo Use Guide

Orally 300-500 mg/m2 daily for 6 weeks for advanced gastrointestinal cancer treatment

Route of Administration: Oral

In Vitro Use Guide

When exposed for 24 h to carmofur (1–100 mM), AC-overexpressing HEK 293 cells showed a markedly reduced ceramide accumulation and cell death relative to control cells subjected to the same treatment.

Name

Type

Language

CARMOFUR

Official Name

English

carmofur [INN]

Common Name

English

CARMOFUR [MI]

Common Name

English

NSC-758963

Code

English

MIFUROL

Brand Name

English

CARMOFUR [JAN]

Common Name

English

CARMOFUR [MART.]

Common Name

English

Carmofur [WHO-DD]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C1557